Is CPN2 p.Arg533Trp (c.1597C>T) pathogenic?

CPN2 p.Arg533Trp (c.1597C>T) is classified Uncertain significance in CPN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1342); Very rare (popmax 0.00334%, amr).

How common is CPN2 p.Arg533Trp (c.1597C>T) in the general population?

CPN2 p.Arg533Trp (c.1597C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about CPN2 p.Arg533Trp (c.1597C>T)?

AlphaMissense predicts likely benign (score 0.1342) — an in-silico prediction, not a clinical call.

CPN2 p.Arg533Trp

c.1597C>T · rs141044584 · VCV2485688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1342 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1342	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -10.14	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -2.2, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 1,634 bp · p 0.047 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,914 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00199% 32/1,610,130 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,957
South Asian	0.0033%	30,316
African / African-American	0.00267%	37,430
European (non-Finnish)	0.00212%	47,110

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CPN2
Protein: p.Arg533Trp
Coding: c.1597C>T
MANE Select: NM_001080513
dbSNP: rs141044584
Type: single nucleotide variant
Location: chr3:194341106 (GRCh38)
Gene constraint: LOEUF 1.831 · pLI 0.20 (gnomAD)
Structure: AlphaFold pLDDT 85.71

Full CPN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPN2 p.Leu14= Benign ★★ same type
CPN2 p.Ala19Val Uncertain significance ★ ⚠ same type
CPN2 p.Ala204Val Uncertain significance ★ ⚠ same type
CPN2 p.Ala351Val Uncertain significance ★ ⚠ same type
CPN2 p.Ala476Thr Uncertain significance ★ ⚠ same type
CPN2 p.Ala477Ser Uncertain significance ★ ⚠ same type
CPN2 p.Ala493Thr Uncertain significance ★ ⚠ same type
CPN2 p.Arg250Cys Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cpn2-p-arg533trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown